Pharmacogenomics focuses on the use of genomic information to optimize drug response and is an important component of precision medicine. Current challenges in the field include the interpretation of rare variant information, the integration of variation across the genes in drug response pathways, and the implementation of pharmacogenomic knowledge in the clinic. A central repository of knowledge is critical in addressing all these challenges. Since 2000, the Pharmacogenomics Knowledgebase (PharmGKB) has become the premier repository of information about how human genetic variation impacts drug response phenotypes. The PharmGKB focuses on the manual curation of knowledge gained from the primary literature and from the careful analysis of large biological data sets. We have extracted information from 9,724 articles, capturing more than 10,843 published associations between genetic variants and drug response phenotypes, covering 591 drugs, 973 genes, and 3,328 unique genetic variations. We create aggregations of this information, including 107 pathways of drug response and metabolism, 54 summaries of very important pharmacogenes, 63 dosing guidelines, and 1,601 clinical annotations summarizing the level of evidence supporting use in clinical practice. We use our position as an independent resource to organize data-sharing consortia, and clinical implementation collaborations. In this proposal, we outline a plan to extend the activities of the PharmGKB by implementing a plan of curation, tool-building and collaborations that address the key challenges to the field. We will expand our curation efforts to increase efficiency of literature-based curation, and add curation of knowledge gathered from deep sequencing of clinical samples. We will focus on curating complex drug responses involving multiple genes which may vary in their coding regions or their regulatory control. We will build an application programming interface that allows us to develop multiple user-interfaces to the knowledge in PharmGKB for different scientific audiences on multiple devices. Finally, we will collaborate with key efforts focused on advancing genomic medicine, where we will bring deep expertise in the use of genomics to improve the precision of drug selection and dosing.